Glucocorticoids, Inhaled Therapeutic Class Review (TCR)

Transcription

1 Glucocorticoids, Inhaled Therapeutic Class Review (TCR) July 31, 2015 No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, digital scanning, or via any information storage or retrieval system without the express written consent of Magellan Rx Management. All requests for permission should be mailed to: Magellan Rx Management Attention: Legal Department 6950 Columbia Gateway Drive Columbia, Maryland The materials contained herein represent the opinions of the collective authors and editors and should not be construed to be the official representation of any professional organization or group, any state Pharmacy and Therapeutics committee, any state Medicaid Agency, or any other clinical committee. This material is not intended to be relied upon as medical advice for specific medical cases and nothing contained herein should be relied upon by any patient, medical professional or layperson seeking information about a specific course of treatment for a specific medical condition. All readers of this material are responsible for independently obtaining medical advice and guidance from their own physician and/or other medical professional in regard to the best course of treatment for their specific medical condition. This publication, inclusive of all forms contained herein, is intended to be educational in nature and is intended to be used for informational purposes only. Send comments and suggestions to PSTCREditor@magellanhealth.com. July 2015

2 FDA-APPROVED INDICATIONS Drug Manufacturer Indication(s) Glucocorticoids beclomethasone HFA Teva Maintenance treatment of asthma as prophylactic therapy inhalation aerosol (QVAR ) 1 (see indicated ages below for each product) budesonide inhalation powder (Pulmicort Flexhaler ) 2 budesonide inhalation suspension (Pulmicort Respules ) 3 ciclesonide inhalation aerosol (Alvesco ) 4 flunisolide HFA (Aerospan ) 5 fluticasone furoate inhalation powder (Arnuity Ellipta) 6 fluticasone propionate inhalation aerosol (Flovent HFA ) 7 fluticasone propionate inhalation powder (Flovent Diskus ) 8 mometasone furoate inhalation powder (Asmanex Twisthaler) 9 mometasone furoate inhalation aerosol (Asmanex HFA) 10 AstraZeneca AstraZeneca, generic Sunovion Acton GlaxoSmithKline GlaxoSmithKline GlaxoSmithKline Merck Merck For asthma patients requiring systemic corticosteroid administration to reduce or eliminate the need for oral systemic corticosteroids Indicated Ages QVAR is for use in patients age five years and older Pulmicort Flexhaler is for use in patients age six years and older Pulmicort Respules are used in patients age 12 months to eight years Flovent HFA and Flovent Diskus are for use in patients age four years and older Asmanex is for use in patients age four years and older Aerospan is for use in patients six years and older Alvesco, Arnuity Ellipta, and Asmanex HFA are for adult and adolescent patients 12 years of age and older Page 2

3 FDA-Approved Indications (continued) budesonide / formoterol inhalation aerosol (Symbicort ) 11 Glucocorticoid/Bronchodilator Combinations Drug Manufacturer Indication(s) AstraZeneca Treatment of asthma in patients 12 years of age and older Maintenance treatment of airflow obstruction in patients with COPD including chronic bronchitis and emphysema fluticasone furoate /vilanterol (Breo Ellipta ) 12 GlaxoSmithKline Long-term, once, maintenance treatment of airflow obstruction in patients with COPD, including chronic bronchitis and/or emphysema To reduce exacerbations of COPD in patients with a history of exacerbations Treatment of asthma in patients 18 years of age and older fluticasone propionate / salmeterol inhalation aerosol (Advair HFA) 13 fluticasone propionate / salmeterol inhalation powder (Advair Diskus) 14 GlaxoSmithKline Treatment of asthma in patients 12 years of age and older GlaxoSmithKline Treatment of asthma in patients four years of age and older Maintenance treatment of airflow obstruction in COPD including chronic bronchitis and emphysema (250 mcg/50 mcg only) To reduce COPD exacerbations in patients with a history of exacerbations (250 mcg/50 mcg only) mometasone / formoterol Merck Treatment of asthma in patients 12 years of age and older inhalation aerosol (Dulera ) 15 The manufacturing, sale, and dispensing of chlorofluorocarbon (CFC) containing inhalers has been phased out by the United States (US) Food and Drug Administration (FDA) to comply with the Montreal Protocol. 16 Inhalers utilizing an alternative inhalant technology, as shown above, have emerged to meet the needs of patients left by the void. 17 For asthma therapy, the combination products budesonide/formoterol (Symbicort), fluticasone propionate/salmeterol (Advair Diskus, Advair HFA), mometasone/formoterol (Dulera), and fluticasone furoate/vilanterol (Breo Ellipta) should only be prescribed for patients not adequately controlled on a long-term asthma control medication, such as an inhaled corticosteroid (ICS), or whose disease severity clearly warrants initiation of treatment with both an ICS and a long-acting beta 2 agonist (LABA). These combination products are not indicated for the relief of acute bronchospasms. OVERVIEW Asthma Prevalence of asthma in the United States continues to rise. In 2010, total asthma prevalence was estimated to be 8.4% of the population, or approximately 25.7 million Americans. 18 Further, the National Health Statistics Report shows that asthma appears to disproportionately affect minority groups, females, children, and individuals of low socioeconomic status which can place significant pressure on public health systems. 19 The National Asthma Education and Prevention Program (NAEPP) has defined asthma as a chronic inflammatory disorder of the airways in which many cells and cellular elements play a role. 20 In susceptible individuals, inflammation may cause recurrent episodes of wheezing, breathlessness, chest tightness, and coughing. These episodes are usually associated with Page 3

4 airflow obstruction that is often reversible, either spontaneously or with treatment. The inflammation also causes an increase in bronchial hyper-responsiveness to a variety of stimuli. Studies have demonstrated the efficacy of inhaled corticosteroids (ICS) in improving lung function, reducing symptoms, reducing frequency and severity of exacerbations, and improving the quality of life (QoL) of patients with asthma. 21,22,23,24,25 The 2007 National Heart, Lung, and Blood Institute, National Institutes of Health (NHLBI, NIH), and the 2015 Global Initiative for Asthma (GINA) state that inhaled glucocorticoids are currently the most effective anti-inflammatory medications for the treatment of persistent asthma. 26,27 The 2015 GINA guidelines offer a control-based management plan to adjust treatment in a continuous cycle of assessment, treatment, and review of the patient s response as it relates to symptom control, future risk of exacerbations, and side effects. 28 Equally important in this process is identifying the patient s own goals regarding their asthma management to ensure improved outcomes. During this continuous cycle, a stepwise treatment approach is offered to achieve control using the patient s current level of control as the baseline. If the patient is not controlled on the current regimen, treatment should be stepped up until control is achieved. If control is maintained for at least three months on the current regimen, treatment can be stepped down to the lowest step and dosage that maintains control. A combination ICS/long-acting beta 2 -agonist (LABA) product is the preferred step-up treatment for adults and adolescents currently on a low dose ICS who continue to have persistent symptoms/exacerbations. The risk of exacerbations can be reduced in adolescents and adults who are using other alternative therapies with treatment of a low dose ICS/formoterol (with beclomethasone or budesonide). For children (six to 11 years of age) with persistent symptoms, an increased ICS dose is preferred over use of an ICS/LABA agent. Page 4

5 Assessment of Asthma Control from 2015 GINA Guidelines 29 Characteristic Well Controlled (all of the following) Partly Controlled (any present in past week) Uncontrolled A. Assessment of symptom control (preferably over four weeks) Daytime symptoms None (Twice or less per week) Limitations of activities None Any Nocturnal symptoms/awakening None Any Need for reliever/rescue treatment None (Twice or less per week) More than twice per week More than twice per week B. Assessment of future risk (risk of exacerbations, fixed airflow limitation, side effects) Three or more features of partly controlled asthma in any week Independent risk factors for exacerbations include (one or more of these risk factors increases risk for exacerbations despite well controlled symptoms): Uncontrolled asthma symptoms, excessive short-acting beta 2- agonist (SABA) use, inadequate ICS, frequent exacerbations in the past, any admission to critical care for asthma, low forced expiratory volume in one second (FEV 1 ), exposure to cigarette smoke/allergens, major psychological or socioeconomic problems, comorbidities, pregnancy, and sputum or blood eosinophilia Fixed air flow limitation risk factors include: Lack of ICS treatment, tobacco/chemical/occupational exposures, and low initial FEV 1 Risk factors for medication side effects include: Frequent oral corticosteroid use, long-term/high dose ICS, taking P450 inhibitors, and poor inhaler technique FEV 1 = forced expiratory volume in one second; ICS = inhaled corticosteroid; LABA = long acting beta 2 -agonist; SABA = short acting beta 2 -agonist Page 5

6 Stepwise Approach to Asthma Control from 2015 GINA Guidelines 30 Step 1 Step 2 Step 3 Adults and Children Six Years of Age And Older As-needed reliever medication Recommended: SABA Alternative Controller: consider low dose ICS One controller AND an as-needed reliever medication Preferred controller: low-dose ICS + SABA Alternative controllers: leukotriene modifier or low dose theophylline* One or two controllers and an as-needed reliever medication Preferred for adolescents and adults: low-dose ICS AND a LABA as maintenance plus as-needed SABA Preferred for children six to 11 years of age: medium dose ICS + as-needed SABA Alternative controllers: medium- or high-dose ICS, OR low-dose ICS + leukotriene modifier, OR Low-dose ICS + sustained-release theophylline* Two or more Scontrollers AND an as-needed reliever medication Preferred t for adolescents and adults: low dose ICS/formoterol as maintenance + reliever treatment; OR medium-dose e ICS + LABA plus as-needed SABA Preferred p for children six to 11 years of age: referral to expert for assessment and advice Alternative controllers: 4 For adults and adolescents: high-dose ICS + LABA may be considered as trial for three to six months when medium-dose ICS/LABA and/or a third controller (e.g., leukotriene modifier OR sustained release theophylline*) Higher level Sof care and/or add-on treatment In addition t to Step 4 treatment add either: e Alternative controller: oral corticosteroids (lowest dose) p Anti-IgE treatment (omalizumab [Xolair ]) 5 * For children six to 11 years of age, theophylline is not recommended. ICS = inhaled corticosteroid; LABA = long acting beta 2 -agonist; SABA = short acting beta 2 -agonist The NAEPP Expert Panel Report-3 (EPR-3) report released in 2007 also recommends a similar classification of asthma severity and control, to guide in the initiation and adjustment of therapy, respectively. 31 Asthma severity and control are defined in terms of two domains, impairment and risk. The distinction between these domains emphasizes the need to consider separately, asthma s effects on quality of life and functional capacity on an ongoing basis (e.g., in the present), along with risks for adverse events, such as exacerbations and progressive loss of pulmonary function. Page 6

7 Stepwise Approach for Managing Persistent Asthma from the NAEPP Expert Panel Report-3 32 Severity of Asthma Step 1 Intermittent Asthma Step 2 Persistent Asthma Step 3 Persistent Asthma Step 4 Persistent Asthma Step 5 Persistent Asthma Step 6 Persistent Asthma No medications needed SABA as needed Adults and Children 12 Years Low-dose ICS Alternative: cromolyn, LTRA, nedocromil, or theophylline Low-dose ICS + LABA OR Medium-dose ICS Alternative: Low-dose ICS and one of the following: LTRA, theophylline, or zileuton Medium-dose ICS + LABA Alternative: Medium-dose ICS and one of the following: LTRA, theophylline, or zileuton (Zyflo) High-dose ICS + LABA Consider omalizumab for patients who have allergies High-dose ICS + LABA + oral corticosteroid Consider omalizumab for patients who have allergies ICS = inhaled corticosteroid; LABA = long acting beta 2 -agonist; LTRA = leukotriene receptor antagonist or leukotriene modifier; SABA = short acting beta 2 -agonist All asthma patients should have a short-acting beta 2 -agonist inhaler for use on an as-needed basis. Page 7

8 Stepwise Approach for Managing Persistent Asthma from the NAEPP Expert Panel Report-3 33 Severity of Asthma Children from Birth to Four Years of Age Step 1 Intermittent Asthma Step 2 Persistent Asthma Step 3 Persistent Asthma Step 4 Persistent Asthma Step 5 Persistent Asthma Step 6 Persistent Asthma No medications needed SABA as needed Now-dose ICS Alternative: cromolyn or montelukast Children Five to 11 Years of Age No medications needed SABA as needed Low-dose ICS Alternative: cromolyn, LTRA, nedocromil, or theophylline Medium-dose ICS Low-dose ICS + LABA OR LTRA OR theophylline OR Medium-dose ICS Medium-dose ICS + LABA OR montelukast High-dose ICS + LABA OR montelukast High-dose ICS + LABA OR montelukast (Singulair ) + oral corticosteroid Medium-dose ICS + LABA Alternative: medium-dose ICS + LTRA OR theophylline High-dose ICS + LABA Alternative: high-dose ICS + LTRA OR theophylline High-dose ICS + LABA + oral corticosteroid Alternative: high-dose ICS + LTRA OR theophylline + oral corticosteroids ICS = inhaled corticosteroid; LABA = long acting beta 2 -agonist; LTRA = leukotriene receptor antagonist or leukotriene modifier; SABA = short acting beta 2 -agonist COPD The 2015 Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines define chronic obstructive pulmonary disease (COPD) as a preventable and treatable disease in which its pulmonary component is characterized by airflow limitation that is not fully reversible. 34 The airflow limitation is usually progressive and associated with an abnormal inflammatory response of the lung to noxious particles or gases. It is estimated that the number of Americans with a COPD diagnosis exceeds 15 million. 35 Bronchodilator therapy (e.g., beta 2 -agonists, anticholinergics, and methylxanthines) is central to symptom management in COPD, and the inhaled route is preferred. The 2015 GOLD guidelines reference that a subset of LABAs (e.g., formoterol and salmeterol) have demonstrated improvement in FEV 1 and quality of life, as well as decreasing dyspnea and exacerbation and hospitalization rates in COPD patients. 36 However, no significant benefit on mortality or the rate of lung function decline has been demonstrated. While most studies indicate that the existing medications for COPD do not modify the long-term decline in lung function, there is limited evidence that regular treatment with LABAs, inhaled corticosteroids (ICS), and their combination can decrease the rate of decline of lung function. Therefore, pharmacotherapy for COPD is mainly used to decrease symptoms and/or complications. Page 8

9 The GOLD guidelines classify COPD patients into four groups based on risk for exacerbation and symptom severity. Patients in Group A are considered to have a low risk for exacerbation and less COPD symptoms; Group B patients have low exacerbation risk and more symptoms; Group C patients are at high risk for COPD exacerbations, but have less symptoms; and Group D patients are at high risk for exacerbation and have more symptoms. First choice therapy for patients in Group A is as-needed use of a short-acting bronchodilator. Long-acting bronchodilators are recommended for patients who fit Group B description. The GOLD guidelines recommend the addition of ICS to long-acting bronchodilator therapy, such as LABA, for patients with severe to very severe COPD represented as Group C and D patients. 37 An ICS in combination with a LABA is more effective than the individual components in reducing exacerbations and improving lung function and health status. Direct head-to-head studies of combination ICS/LABA and ICS/long-acting anticholinergics are widely absent making comparison and differentiation difficult. 38 A Cochrane Review suggests no significant difference in mortality or lung function (FEV 1 ) between tiotropium, a long-acting anticholinergic agent, and LABAs; however, statistically significant differences in the number of patients experiencing one or more exacerbations were seen in favor of tiotropium, particularly when compared against salmeterol (Odds ratio [OR] 0.86; 95% confidence interval [CI], ). 39 Tiotropium and related anticholinergic products are reviewed under a separate Therapeutic Class Review. PHARMACOLOGY 40,41,42,43,44,45,46,47,48,49 Corticosteroids suppress the cytokine generation, recruitment of airway eosinophils, and release of inflammatory mediators. These agents thereby block late-phase reaction to allergens, reduce airway hyperresponsiveness, and inhibit inflammatory cell migration and activation. 50 Because systemic corticosteroids have a high incidence of adverse reactions, inhaled corticosteroids (ICS) are preferred for asthma. Advair is a combination product containing a long-acting beta 2 -agonist (LABA), salmeterol DPI (Serevent) and a corticosteroid, fluticasone (as propionate). Breo Ellipta also contains the ICS fluticasone (as furoate), as well as the LABA vilanterol. Symbicort is a combination product containing a LABA, formoterol, and an ICS, budesonide. Dulera is a combination product containing the LABA, formoterol and the ICS, mometasone. Formoterol, vilanterol, and salmeterol selectively bind to the beta 2 -receptors in the bronchial smooth muscle, leading to bronchial relaxation and a decrease in the release of mediators of immediate hypersensitivity from mast cells. Delivery and Deposition The selection of a delivery system and the patients ability to use the device properly are critical factors in determining clinical success of inhaled corticosteroid therapy. Delivery systems can significantly affect both topical and systemic activity of ICS. 51,52 Metered dose inhalers (MDIs) are pressurized spray inhalers, available in suspension and solution, for which the user has to press down on the metal canister to release the medicine and then inhale. MDIs deliver approximately 15 to 35% of the administered dose to the lungs. Spacer chambers can be attached to MDIs to make them easier to use by people who find it hard to coordinate the press-andbreathe action. When using the spacer, the user can take several breaths to inhale the medicine, which is held in the chamber, so that it is more likely that the proper amount of medicine will reach the airways. MDIs with CFC propellants are no longer being actively marketed. Page 9

10 Dry-powder inhalers (DPIs) are breath-actuated devices that release the medicine in the form of a dry powder when the user breathes in. Although DPIs minimize the potential difficulties in coordinating the press-and-breathe action of the MDI, these delivery systems tend to result in more dosage variations than MDIs at low inspiratory flow rates (less than 20 L/min). Nebulizer therapy is not the recommended form of administration for most patients. 53 It is considered inferior to an MDI with spacer because of the inconvenience, decreased drug deposition, higher risk of side effects, and potentially higher cost. It may be considered an alternative in cases where patients lack the coordination to use the MDI with spacer, particularly in the very young and the very old. PHARMACOKINETICS 54,55,56,57,58,59,60,61,62,63 Several comparative studies have demonstrated that, when given in equipotent anti-inflammatory doses, fluticasone propionate (Flovent) and budesonide (Pulmicort) have less systemic effect, as measured by plasma cortisol, than the other agents. 64,65,66,67,68 There is, however, considerable intersubject variability in the rate of absorption of these agents from the lungs. 69 The NAEPP guidelines provide information regarding the relative potencies and dosages of each of the available agents, as seen in the table below. 70 It should be noted that these are not the FDA-approved doses, but rather those doses shown to be clinically effective and recommended by the NHLBI. Mometasone (Asmanex) for pediatrics and ciclesonide (Alvesco) were approved after the release of the 2007 NAEPP report and are therefore not contained in the following comparative chart. However, since 2008, mometasone and ciclesonide have been included in the GINA guidelines. Flunisolide (Aerospan) became commercially available in 2014 and is not addressed in the 2015 GINA guidelines. Page 10

11 NAEPP Expert Panel Report-3 Estimated Comparative Daily Dosages for Inhaled Corticosteroids (mcg/day) 71 Drug beclomethasone HFA inhalation aerosol (QVAR) budesonide inhalation powder (Pulmicort) budesonide inhaled suspension (Pulmicort Respules) fluticasone propionate HFA inhalation aerosol (Flovent HFA) mometasone inhalation powder (Asmanex Twisthaler) n/a= not available Adults and Children 12 Years of Age Lowdose Mediumdose Highdose Children (Five to 11 Years of Age) Lowdose Mediumdose Highdose > > > >600 1,200 >1, > >800 n/a n/a n/a 0.5 mg (ages 5 to 8 years) 1 mg (ages 5 to 8 years) 2 mg (ages 5 to 8 years) > > > >400 n/a n/a n/a Most of the agents in this class are recommended for twice use. The exceptions to this are mometasone (Asmanex DPI) and fluticasone furoate inhalation powder (Arnuity Ellipta), which can be dosed once GINA Guidelines for Equipotent Dosages of Inhaled Corticosteroids (mcg/day) 72 Drug beclomethasone HFA inhalation aerosol (QVAR) budesonide inhalation powder (Pulmicort) budesonide respules (Pulmicort Respules) ciclesonide inhalation aerosol (Alvesco) fluticasone propionate inhalation aerosol (Flovent) mometasone inhalation powder (Asmanex) Lowdose Adults Mediumdose High-dose Lowdose Children Mediumdose Highdose > >500 1, > > > >800 1, > >400 n/a n/a n/a >500 1,000 >1, > >320 1, > > > >500 1, > > Page 11

12 Onset of Action Drug Onset of action Maximum benefit Glucocorticoids beclomethasone HFA inhalation aerosol (QVAR) 73 one to two weeks three to four weeks budesonide inhalation powder (Pulmicort 24 hours one to two weeks Flexhaler) 74 budesonide suspension (Pulmicort Respules) 75 two to eight days four to six weeks ciclesonide inhalation aerosol (Alvesco) four weeks or longer flunisolide HFA inhalation aerosol (Aerospan) three to four weeks fluticasone furoate inhalation powder (Arnuity variable two weeks or longer Ellipta) 78 fluticasone propionate inhalation aerosol (Flovent 24 hours variable time to onset one to two weeks or longer HFA) 79 fluticasone propionate powder for inhalation 24 hours variable time to onset one to two weeks or longer (Flovent Diskus) 80 mometasone inhalation powder (Asmanex) 81 one to 2.5 hours one to two weeks or longer mometasone furoate inhalation aerosol (Asmanex variable one week or longer HFA) 82 budesonide/formoterol inhalation aerosol (Symbicort) 83 Glucocorticoids/Bronchodilator combinations 15 minutes for asthma, five minutes for COPD two weeks or longer fluticasone furoate/vilanterol (Breo Ellipta) minutes nr fluticasone propionate/salmeterol inhalation powder minutes one week or longer (Advair Diskus) 85 fluticasone propionate/salmeterol inhalation aerosol minutes one week or longer (Advair HFA) 86 mometasone/formoterol inhalation aerosol (Dulera) 87 variable one week or longer CONTRAINDICATIONS/WARNINGS 88,89,90,91,92,93,94,95,96,97,98 All of these agents are contraindicated in the primary treatment of status asthmaticus or other acute episodes of asthma or COPD where intensive measures are required. A black box warning exists for all long-acting beta 2 agonists (LABAs; e.g., salmeterol and formoterol), as well as all combination products that contain them [e.g., fluticasone propionate/salmeterol (Advair HFA, Advair Diskus), budesonide/formoterol (Symbicort), mometasone/formoterol (Dulera), fluticasone furoate/vilanterol (Breo Ellipta)]. For Advair Diskus, Advair HFA, Symbicort, Dulera, and Breo Ellipta, the boxed warnings warn of the following: LABAs increase the risk of asthma-related deaths. Available data from controlled clinical trials suggest that LABAs increase the risk of asthmarelated hospitalization in pediatric and adolescent patients. These findings are considered a class effect of all LABAs. Page 12

13 When treating patients with asthma these agents should be prescribed for only those patients not adequately controlled on a long-term asthma control medication, such as an inhaled corticosteroid (ICS), or whose disease severity clearly warrants initiation of treatment with both an ICS and LABA. Once asthma control is achieved and maintained, assess the patient at regular intervals and step down therapy (e.g., discontinue Advair, Symbicort, Dulera, or Breo Ellipta) if possible without loss of asthma control, and maintain the patient on a long-term asthma control medication, such as an ICS. Do not use these agents for patients whose asthma is adequately controlled on low or medium dose ICS. The inhalation powder formulations of fluticasone furoate (Arnuity Ellipta), fluticasone propionate (Flovent Diskus), fluticasone furoate/vilanterol (Breo Ellipta) and fluticasone propionate/salmeterol (Advair Diskus) are contraindicated in patients who have a severe hypersensitivity to milk proteins as these products contain milk proteins. Decreased bone mineral density (BMD) has been observed with the long-term administration of products containing inhaled glucocorticoids. 99 The clinical significance of small changes in BMD with regard to long-term outcomes is unknown. Patients with major risk factors for decreased bone mineral content, such as prolonged immobilization, family history of osteoporosis, postmenopausal status, tobacco use, advanced age, poor nutrition, or chronic use of drugs that can reduce bone mass (e.g., anticonvulsants, oral corticosteroids, etc.), should be monitored and treated according to the current standards of care. There have been postmarketing reports of esophageal candidiasis for fluticasone propionate (Flovent Diskus, Flovent HFA). Risk Evaluation and Mitigation Strategy The products that contain a LABA (Advair Diskus, Advair HFA, Breo Ellipta, Dulera, and Symbicort) do not have REMS requirements by the FDA; however, a medication guide has been included in the product labeling. DRUG INTERACTIONS 100,101,102,103,104,105,106,107,108 The main route of metabolism for many corticosteroids is via the cytochrome P450 isoenzyme 3A4. Inhibitors of CYP3A4 (ritonavir, ketoconazole, itraconazole, clarithromycin, erythromycin) may increase the plasma concentration of inhaled corticosteroids (ICS). Fluticasone propionate (Flovent) use in combination with ritonavir has been associated with systemic corticosteroid effects, such as Cushing s syndrome and adrenal suppression. Products containing salmeterol, formoterol, or vilanterol (Advair Diskus, Advair HFA, Breo Ellipta, Dulera, Symbicort) should be administered with caution to patients being treated with monoamine oxidase inhibitors, tricyclic antidepressants, or drugs known to prolong the QTc interval or within two weeks of discontinuation of such agents, because the action of the long-acting beta 2 agonist (LABA), on the cardiovascular system may be potentiated by these agents. Concomitant treatment with xanthine derivatives or diuretics may potentiate any hypokalemic effect of the LABA. Beta-blockers and diuretics should be used caution with drugs containing a LABA. Beta-blockers may interfere with the bronchodilatory effect of the LABA resulting in bronchospasm. Electrolyte abnormalities, such as hypokalemia, exacerbated by diuretics may be enhanced by concomitant beta-agonist usage. Page 13

14 ADVERSE EFFECTS Drug Cough Headache Nausea Glucocorticoids Oral candidiasis Pharyngitis Upper respiratory infection beclomethasone HFA inhalation aerosol (QVAR) budesonide inhalation powder (Pulmicort nr nr Flexhaler) 110 budesonide suspension >3 nr nr > (Pulmicort Respules) ciclesonide inhalation aerosol 112 < < 1 < (Alvesco) flunisolide HFA inhalation aerosol (Aerospan) nr nr nr fluticasone furoate inhalation powder (Arnuity Ellipta) reported < fluticasone propionate powder for inhalation < (Flovent Diskus) 115 fluticasone propionate inhalation aerosol reported (Flovent HFA) 116 mometasone inhalation 117 nr powder (Asmanex) mometasone furoate inhalation aerosol (Asmanex nr 3 5 reported reported 5 8 nr HFA) 118 Glucocorticoid/Bronchodilator Combinations budesonide/ formoterol inhalation aerosol reported reported (Symbicort) 119 fluticasone propionate/ salmeterol inhalation powder (Advair Diskus) 120 fluticasone propionate/salmeterol inhalation aerosol (Advair reported nr 16 HFA) 121 fluticasone furoate/vilanterol nr 5-7 nr (nr in asthma) (Breo Ellipta) 122 mometasone/ formoterol 123 nr nr nr inhalation aerosol (Dulera) Adverse effects are reported as a percentage. Adverse effects are obtained from package inserts and are not meant to be comparative or all inclusive. nr = not reported. Page 14

15 In 2010, the FDA issued new recommendations on the safe use of LABAs in the treatment of asthma, which also applied to the combination products of budesonide/formoterol (Symbicort), mometasone/formoterol (Dulera), and fluticasone propionate/salmeterol (Advair Diskus, Advair HFA). 124 The FDA recommends against the use of LABAs without the use of an asthma controller medication, such as an inhaled corticosteroid (ICS). Also, LABAs should be used for the shortest duration of time required to achieve control of asthma symptoms and discontinued, if possible, once asthma control is achieved. They should be used long-term only in patients whose asthma is not adequately controlled on asthma controller medications. The REMS for LABAs includes a revised Medication Guide written specifically for patients, and a plan to educate healthcare professionals about the appropriate use of LABAs. In 2012, at the request of various manufacturers, the FDA released a number of products containing LABAs from their REMS requirements. These changes are outlined in the REMS section of this document. Additionally, in April 2011, to further evaluate the safety of LABAs when used in combination with ICS for the treatment of asthma, the FDA is requiring the manufacturers of LABAs to conduct five randomized, double-blind, controlled clinical trials to further evaluate the safety of LABAs when used in combination with ICS in comparison to ICS alone. These clinical trials began in 2011 and the FDA expects to receive results in SPECIAL POPULATIONS 126,127,128,129,130,131,132,133,134,135,136,137,138 Pediatrics Safety and effectiveness of budesonide/formoterol (Symbicort), ciclesonide (Alvesco), fluticasone furoate (Arnuity Ellipta), fluticasone propionate/salmeterol (Advair HFA), mometasone furoate (Asmanex HFA), and mometasone/formoterol (Dulera) in children under age 12 have not been proven. Safety and effectiveness of budesonide (Pulmicort Flexhaler) in children less than six years have not been established. Beclomethasone (QVAR) in children less than five years has not been proven safe or effective. Flunisolide (Aerospan) in children less than six years has not been proven safe or effective. Fluticasone propionate/salmeterol (Advair Diskus) and fluticasone propionate (Flovent HFA, Flovent Diskus) in children younger than four years have not been proven safe or effective. Mometasone (Asmanex) is approved for maintenance treatment of asthma as prophylactic therapy for children age four years and older. The safety and efficacy of fluticasone furoate/vilanterol (Breo Ellipta) has not been established in pediatric patients. Budesonide respules (Pulmicort Respules) are indicated specifically for children between 12 months and eight years of age. Pregnancy All products in this category are Pregnancy Category C except budesonide (Pulmicort), which is Pregnancy Category B. Page 15

16 Hepatic Impairment Close monitoring of patients using fluticasone propionate/salmeterol (Advair) or budesonide/formoterol (Symbicort) who have hepatic impairment is recommended due to accumulation of both active ingredients. Caution is advised when fluticasone furoate/vilanterol (Breo Ellipta) and fluticasone furoate (Arnuity Ellipta) are administered to patients with moderate to severe hepatic impairment. Formal studies of fluticasone propionate (Flovent Diskus, Flovent HFA) have not been performed in subjects with hepatic impairment; however, since it is predominantly metabolized by the liver, hepatitic impairment may lead to increased plasma concentrations; caution should be used in patients with hepatic impairment. Vilanterol is unaffected by hepatic impairment. Patients should be monitored for corticosteroid-related side effects. DOSAGES Drug beclomethasone HFA inhalation aerosol (QVAR) 139 budesonide inhalation powder (Pulmicort Flexhaler) 140 budesonide inhalation suspension (Pulmicort Respules) 141 Adult Doses Pediatric Doses Initial Maximum Initial Maximum mcg twice (previous bronchodilator use alone); mcg twice (previous inhaled corticosteroid therapy) 360 mcg twice 320 mcg twice 720 mcg twice Glucocorticoids Age 5 to 11 years: 40 mcg twice Age 6 to 17 years: 180 mcg twice Age 12 months to 8 years: Prior bronchodilator alone: 500 mcg once or 250 mcg twice Prior ICS: 500 mcg once or 250 to 500 mcg twice Prior oral glucocorticoid: 500 mcg twice or 1,000 mcg once Age 5 to 11 years: 80 mcg twice Age 6 to 17 years: 360 mcg twice Availability 40 mcg and 80 mcg MDI with HFA propellant (100 actuations per canister) Dose counter available for all strengths 90 mcg and 180 mcg DPI (60 and 120 actuations per canister, respectively) Dose counter available for all strengths , 500, 1,000 mcg per 2 ml respules via jet nebulizer Page 16

17 Dosages (continued) Drug ciclesonide inhalation aerosol (Alvesco) 142 flunisolide HFA inhalation aerosol (Aerospan) 143 fluticasone furoate inhalation powder (Arnuity Ellipta) 144 Adult Doses Pediatric Doses Initial Maximum Initial Maximum 80 mcg twice (patients who received bronchodilator alone) 80 mcg twice (patients who received inhaled corticosteroid) 320 mcg twice (patients who received oral corticosteroids) 160 mcg twice One Inhalation of 100 mcg or 200 mcg once (starting dose based on prior asthma therapy and disease severity) * Higher doses have not been studied. 160 mcg twice 320 mcg twice 320 mcg twice 320 mcg twice * Glucocorticoids Age 12 years and older: 80 mcg twice (patients who received bronchodilator alone) Age 12 years and older: 80 mcg twice (patients who received inhaled corticosteroid) Age 12 years and older: 120 mcg twice (patients who received oral corticosteroid) 80 mcg twice 200 mcg Age 12 years and older: one Inhalation of 100 mcg or 200 mcg once Age 12 years and older: 160 mcg twice Age 12 years and older: 320 mcg twice Age 12 years and older: 320 mcg twice 160 mcg twice * Age 12 years and older: 200 mcg Availability 80 mcg or 160 mcg MDI with HFA propellant (80 mcg is available as 60 actuations per canister) (160 mcg MDI is available as 60 actuations per canister) Dose counter available for all strengths 80 mcg or 160 mcg MDI with HFA propellant (5.1 g canister has 60 actuations per canister) (8.9 g canister has 120 actuations per canister) 100 or 200 mcg blister strip of inhalation only powder Page 17

18 Dosages (continued) Drug fluticasone propionate inhalation aerosol (Flovent HFA) 145 fluticasone propionate inhalation powder (Flovent Diskus) 146 mometasone furoate inhalation aerosol (Asmanex HFA) 147 Adult Doses Pediatric Doses Initial Maximum Initial Maximum 88 mcg twice (patients who received bronchodilator alone); mcg twice (patients who used ICS); 440 mcg twice (patients who used oral corticosteroids) 100 mcg twice (patients who received bronchodilators alone) mcg twice (patients who used ICS) 500 1,000 mcg twice (patients who used oral corticosteroids) Based on prior asthma therapy: two inhalations of 100 mcg or 200 mcg twice 440 mcg twice 440 mcg twice 880 mcg twice 500 mcg twice 500 mcg twice 1,000 mcg twice 400 mcg twice Glucocorticoids Age 4 to 11 years: 88 mcg twice Age 4 to 11 years: 50 mcg twice (when prior therapy is with bronchodilator alone or inhaled corticosteroid) Age 12 years and older: two inhalations of 100 mcg or 200 mcg twice Age 4 to 11 years: 88 mcg twice Age 4 to 11 years: 100 mcg twice Age 12 years and older: 400 mcg twice Availability 44, 110, 220 mcg MDI with HFA propellant (120 actuations per canister) Dose counter available for all strengths 50, 100, 250 mcg blister units (60 blisters per pack) Dose counter available for all strengths Pressurized meter dose inhaler available in two strengths: 100 mcg or 200 mcg per actuation Page 18

19 Dosages (continued) Drug mometasone inhalation powder (Asmanex Twisthaler) 148 budesonide/formoterol inhalation aerosol (Symbicort) 149 fluticasone furoate/vilanterol inhalation powder (Breo Ellipta) 150 The recommended starting dosages for asthma are based on prior asthma therapy (ICS) Adult Doses Pediatric Doses Initial Maximum Initial Maximum 220 mcg in evening (if on bronchodilator alone or inhaled corticosteroid) or 440 mcg twice (if on oral corticosteroid) Two inhalations twice of 80 mcg/ 4.5 mcg or 160 mcg/ 4.5 mcg Asthma: Low-to mid-dose ICS: One inhalation of 100 mcg/25 mcg once Mid- to high-dose ICS: One inhalation of 200 /25 mcg once COPD: One inhalation of 100 mcg/25 mcg once Glucocorticoids 440 mcg (single or divided doses) or 880 mcg Age 12 years and older: 220 mcg in evening (if on bronchodilator alone or inhaled steroid) or 440 mcg twice (if on oral corticosteroid) Age 4 to 11 years of age: 110 mcg once in the evening Age 12 years and older: 440 mcg (single or divided doses) or 880 mcg Age 4 to 11 years of age: 110 mcg once in the evening Glucocorticoid/Bronchodilator Combinations Two inhalations twice of 160 mcg/ 4.5 mcg Asthma: One inhalation of 200 mcg /25 mcg once COPD: One inhalation of 100 mcg/25 mcg once Age 12 years and older: two inhalations twice of 80 mcg/ 4.5 mcg or 160 mcg/ 4.5 mcg Age 12 years and older: two inhalations twice of 160 mcg/ 4.5 mcg Availability 110 or 220 mcg DPI (Available in 100 or 200 actuations per unit, respectively) Dose counter available for all strengths 80/4.5 and 160/4.5 mcg per actuation MDI with HFA propellant (120 actuations per canister) Dose counter available for all strengths 100/25 mcg per inhalation and 200/25 mcg per inhalation Dose counter available Page 19

20 Dosages (continued) Drug fluticasone propionate/salmeterol inhalation aerosol (Advair HFA) 151 fluticasone propionate/salmeterol inhalation powder (Advair Diskus) 152 mometasone/formoterol inhalation aerosol (Dulera) 153 The recommended starting dosages are based on prior asthma therapy Adult Doses Pediatric Doses Initial Maximum Initial Maximum Glucocorticoid/Bronchodilator Combinations Two inhalations of 45 mcg/ 21 mcg twice or 115 mcg/21 mcg twice or 230 mcg/ 21 mcg twice Asthma: 100 mcg/ 50 mcg twice to 500 mcg/ 50 mcg twice Maintenance treatment of COPD: 1 inhalation twice of 250 mcg/50 mcg For medium dose ICS: two inhalations of 100 mcg/5 mcg twice For high dose ICS: two inhalations of 200 mcg/5 mcg twice Two inhalations of 230 mcg/ 21 mcg twice Asthma: 500 mcg/ 50 mcg twice Dose ICS: two inhalations of 100 mcg/5 mcg twice For high dose ICS: two inhalations of 200 mcg/5 mcg twice Age 12 years and older: two inhalations of 45 mcg/ 21 mcg twice or 115 mcg/ 21 mcg twice or 230 mcg/ 21 mcg twice Age 4-11 years 100 mcg/ 50 mcg twice Age 12 years and older: one inhalation twice of 100/50, 250/50, or 500/50 mcg Age 12 years and older: For medium dose ICS: two inhalations of 100 mcg/5 mcg twice For high dose ICS: two inhalations of 200 mcg/5 mcg twice Age 12 years and older: two inhalations of 230 mcg/ 21 mcg twice -- Age 12 years and older: For medium dose ICS: two inhalations of 100 mcg/5 mcg twice For high dose ICS: two inhalations of 200 mcg/5 mcg twice Availability 45/21, 115/21, and 230/21 mcg per actuation MDI with HFA propellant (120 actuations per canister) Dose counter available for all strengths 100/50, 250/50, and 500/50 mcg per actuation Diskus DPI (60 blisters) Dose counter available for all strengths 100/5 and 200/5 mcg per actuation Dose counter available for all strengths CLINICAL TRIALS Search Strategy Studies were identified through searches performed on PubMed and review of information sent by manufacturers. Search strategy included the FDA-approved use of all drugs in this class. Randomized, controlled, comparative trials are considered the most relevant in this category. Studies included for Page 20

21 analysis in the review were published in English, performed with human participants, and randomly allocated participants to comparison groups. In addition, studies must contain clearly stated, predetermined outcome measure(s) of known or probable clinical importance, use data analysis techniques consistent with the study question, and include follow-up (endpoint assessment) of at least 80% of participants entering the investigation. Despite some inherent bias found in all studies, including those sponsored and/or funded by pharmaceutical manufacturers, the studies in this therapeutic class review were determined to have results or conclusions that do not suggest systematic error in their experimental study design. While the potential influence of manufacturer sponsorship and/or funding must be considered, the studies in this review have also been evaluated for validity and importance. Asthma beclomethasone MDI (QVAR) versus placebo The Treating Children to Prevent Exacerbations of Asthma (TREXA) study was a multi-center, 44-week, randomized, double-blind, placebo-controlled trial conducted in 288 children and adolescents with mild persistent asthma aged six to 18 years to evaluate the impact and severity of asthma exacerbations in patients who are receiving various combinations of medications for and rescue use. 154 Patients were randomly assigned to one of four treatment groups: twice beclomethasone with beclomethasone plus albuterol as rescue (combined group, n=71); twice beclomethasone with placebo plus albuterol as rescue ( beclomethasone group, n=72); twice placebo with beclomethasone plus albuterol as rescue (rescue beclomethasone group, n=71); and twice placebo with placebo plus albuterol as rescue (placebo group, n=74). Twice beclomethasone treatment was one puff of beclomethasone (40 mcg per puff) or placebo given in the morning and evening. Rescue beclomethasone treatment was two puffs of beclomethasone or placebo for each two puffs of albuterol (180 mcg) needed for symptom relief. The primary outcome was time to first exacerbation that required oral corticosteroids. A secondary outcome measured linear growth. Analysis was by intention to treat. Compared with the placebo group (49%; 95% confidence interval [CI], 37-61), the frequency of exacerbations was lower in the (28%; 95% CI, 18-40%; p=0.03), combined (31%; 95% CI, 21-43%; p=0.07), and rescue (35%; 95% CI, 24-47%; p=0.07) groups. Frequency of treatment failure was 23% (95% CI, 14-43%) in the placebo group, compared with 5.6% (95% CI, %) in the combined (p=0.012), 2.8% (95% CI, 0-10%) in the (p=0.009), and 8.5% (95% CI, 2-15%) in the rescue (p=0.024) groups. Compared with the placebo group, linear growth was 1.1 cm (SD 0.3) less in the combined and arms (p<0.0001), but not the rescue group (p=0.26). Only two individuals had severe adverse events; one in the beclomethasone group had viral meningitis and one in the combined group had bronchitis. The authors concluded that children with mild persistent asthma should not be treated with rescue albuterol alone and the most effective treatment to prevent exacerbations is inhaled corticosteroids (ICS). ICS as rescue medication with albuterol might be an effective step-down strategy for children with well controlled, mild asthma because it is more effective at reducing exacerbations than is use of rescue albuterol alone. Use of ICS treatment and related side-effects, such as growth impairment, can therefore be avoided. This study was funded by the National Heart, Lung and Blood Institute. Page 21

22 budesonide/formoterol MDI (Symbicort) versus budesonide DPI (Pulmicort) A double-blind, randomized, 12-week study conducted in 619 patients ages 12 and older with mild to moderate asthma to evaluate the efficacy and tolerability of once budesonide/formoterol versus once budesonide in patients stable with twice budesonide/formoterol. 155 After an initial four to five weeks of two inhalations twice budesonide/formoterol 80 mcg/4.5 mcg ( dose of 320 mcg/18 mcg), stable patients were randomized to one of four treatment groups. These groups included: two inhalations of twice of budesonide/formoterol 80 mcg/4.5 mcg ( dose 320 mcg/18 mcg); two inhalations once in the evening of budesonide/formoterol 160/4.5 mcg or 80/4.5 mcg ( dose of 320 mcg/9 mcg or 160/4.5 mcg); or two inhalations once of budesonide 160 mcg ( dose of 320 mcg). All budesonide/formoterol groups maintained significantly more favorable evening pre-dose forced expiratory volume in one second (FEV 1 ), morning peak expiratory flow (PEF), daytime/nighttime asthma symptoms, nighttime rescue medication use, and rescue medication-free days versus budesonide. Variables evaluated during the end of the once dosing interval included evening pre-dose FEV 1, evening PEF, daytime asthma symptoms, and daytime rescue medication use. They significantly favored twice budesonide/formoterol versus all treatments. Twice budesonide/formoterol demonstrated significantly more favorable results for symptomfree and asthma control days versus all treatments and awakening-free nights versus budesonide. Asthma Quality of Life Questionnaire and Asthma Control Questionnaire results significantly favored twice- budesonide/formoterol versus budesonide (p 0.018). All treatments were well tolerated. A double-blind, randomized, 12-week multicenter study was conducted in 521 patients ages six to 15 years with mild/moderate persistent asthma to assess the efficacy and tolerability of once budesonide/formoterol metered-dose inhaler (MDI) versus budesonide MDI (primary) and twice budesonide/formoterol MDI (secondary) in children/adolescents with asthma who have been stabilized with twice budesonide/formoterol MDI. 156 Patients had been stabilized during a four to five week run-in with two inhalations twice of budesonide/formoterol 40/4.5 mcg inhalations (160/18 mcg ). These patients were randomized to either continue on the stabilization regimen, to receive a reduced dose of two inhalations once every evening of budesonide/formoterol 80/4.5 mcg (160/9 mcg ), or two inhalations once every evening of budesonide 80 mcg (160 mcg ). The once or twice regimens of budesonide/formoterol were more effective than budesonide for evening PEF (primary variable) at the end of the 24 hour once dosing interval (p 0.027). Twice budesonide/formoterol demonstrated better efficacy versus once treatments for evening pre-dose FEV 1 (p 0.011), versus budesonide for daytime/nighttime rescue medication (p 0.023), and versus once budesonide/formoterol for daytime rescue medication (last 12 hours of once dosing) (p=0.032). There were no significant between-group differences for daytime/nighttime asthma symptoms, nighttime awakenings attributed to asthma, or health-related quality of life. Fewer patients experienced asthma worsening based on predefined criteria with twice budesonide/formoterol (8.2%) versus once budesonide (15.5%) (p=0.036) or once budesonide/formoterol (19.6%) (p=0.002). All treatments were well tolerated. budesonide/formoterol MDI (Symbicort) versus budesonide DPI (Pulmicort) versus formoterol MDI (Foradil) versus budesonide (Pulmicort) + formoterol (Foradil) versus placebo A 12-week, randomized, double-blind, double-dummy, placebo-controlled study was conducted to compare the efficacy and safety of budesonide/formoterol to each of its individual ingredients [budesonide, formoterol, or budesonide + formoterol] as well as to placebo. 157 Five hundred ninety-six Page 22

23 patients ages 12 years and older with moderate to severe persistent asthma and previously receiving an ICS were placed on budesonide 160 mcg twice. After two weeks, they were randomized to budesonide/formoterol 160/4.5 mcg twice ; budesonide 160 mcg twice + formoterol 4.5 mcg twice ; budesonide 160 mcg twice ; formoterol 4.5 mcg twice ; or placebo twice. The primary efficacy endpoints were mean change from baseline of FEV 1 and mean change from baseline in 12-hour FEV 1. The results were similar in the budesonide/formoterol and the budesonide + formoterol groups in all measures. The budesonide/formoterol group showed greater improvement in FEV 1 (p 0.049) than the individual budesonide, formoterol, and placebo. Also, fewer patients on budesonide/formoterol experienced worsening asthma symptoms (p 0.025). All of the treatments were well tolerated with similar safety profiles. A 12-week, randomized, double-blind, double-dummy, placebo-controlled, multicenter trial of 596 adult patients (ages 12 and older) with moderate to severe persistent asthma was conducted to evaluate patient reported outcomes (PROs) related to asthma therapy. 158 Patients received budesonide 160 mcg twice for the first two weeks. They were then randomized to receive two inhalations twice of one of five treatment arms: budesonide/formoterol 160/4.5 mcg; budesonide 160 mcg plus formoterol DPI 4.5 mcg; budesonide 160 mcg; formoterol DPI 4.5 mcg; or placebo. PROs were assessed in 553 patients 18 years or older using the standardized Asthma Quality of Life Questionnaire (AQLQ[S]), Medical Outcomes Survey (MOS) Sleep Scale, Patient Satisfaction with Asthma Medication (PSAM) questionnaire, diary data, and global assessments. Patients receiving budesonide/formoterol reported significantly greater improvements from baseline on the AQLQ(S) and asthma control variables (based on symptoms and rescue medication use; all p<0.001) versus placebo. Clinically important improvements (increase of 0.5 points) from baseline to end of treatment in AQLQ(S) overall scores were achieved by 43.6% of patients receiving budesonide/formoterol versus 22.6% of patients receiving placebo (p=0.001). The MOS Sleep Scale scores generally showed no differences among treatment groups. Patients receiving budesonide/formoterol had significantly greater PSAM questionnaire scores and better outcomes on physician-patient global assessments at end of treatment versus placebo (all p 0.001). budesonide/formoterol MDI (Symbicort) versus budesonide (Pulmicort) versus formoterol (Foradil) versus placebo A 12-week, multicenter, double-blind, randomized, placebo-controlled, double-dummy study was conducted in 480 patients age 12 years or older with mild to moderate persistent asthma treated with ICS for four weeks or more and with an FEV 1 of 60 to 90%. 159 After a two-week washout period, patients received either budesonide/formoterol 80/4.5 twice (n=123), budesonide 80 mcg twice (n=121), formoterol 4.5 mcg twice (n=114), or placebo (n=122). At the end of treatment, greater increases in FEV 1 occurred in the budesonide/formoterol group versus all of the other groups (0.37 versus 0.23, 0.17, and 0.03 L, respectively; p<0.005). Fewer patients receiving budesonide/formoterol withdrew due to worsening asthma versus the formoterol (42.1 and 18.4%) and placebo (56.6 versus 32.8%) groups. However, the results were similar, according to the authors, with respect to worsening asthma between the budesonide/formoterol and budesonide groups (21.5 versus 6.6%). The authors determined that in adults and adolescents with mild to moderate persistent asthma that twice budesonide/formoterol resulted in improved pulmonary function versus its component ingredients alone. All of the study drugs were well tolerated. Page 23